Neurodegenerative diseases with Parkinsonian Syndromes are disorders affecting the central nervous system and that are associated with akinesia and several other neurological disorders. The proportion of affected persons is about 0.3% of the whole population in industrialized countries.
Neurodegenerative diseases with Parkinsonian Syndromes usually affect people over the age of 50 except for a person suffering from an early-onset variant. Early symptoms of neurodegenerative diseases with Parkinsonian Syndromes are subtle and occur gradually. The primary symptoms of these disorders are: tremor or trembling in hands, arms, legs, jaw, and face; rigidity or stiffness of the limbs and trunk; bradykinesia, or slowness of movement, and postural instability, or impaired balance and coordination. Other symptoms may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions. As these symptoms become more pronounced, patients may have difficulty walking, talking or completing other tasks.
Neurodegenerative diseases with Parkinsonian Syndromes such as Parkinson Disease (PD) comprise motor symptoms and non-motor symptoms.
Non-motor symptoms may include autonomic dysfunction, cognitive (impairment of cognitive and executive performances) and behavioral problems leading sometimes to dementia, and sensory, sleep and emotional problems (mostly depression). Treatment of these non-motor symptoms is not yet standardized although some drugs have been proposed such as antidepressant drugs (depression), clozapine (illusions, hallucinations), cholinesterase inhibitors (dementia treatment) and modafinil (sleep problems treatment).
The motor symptoms of degenerative disorders involving the dopaminergic system such as PD are collectively called “Parkinsonian Syndromes”. Motor symptoms include, without limitation, bradykinesia, tremor at rest, rigidity or stiffness, shaking, slowness of movement and postural instability. Idiopathic Parkinson Disease is the most common cause of Parkinsonian Syndrome (about 65%). Other causes include, without limitation, Progressive Supranuclear Palsy, Multiple System Atrophy, Corticobasal Degeneration and Lewy Body Dementia, Wilson's disease.
Neurodegenerative diseases with Parkinsonian Syndromes are characterized by the loss of pigmented dopaminergic neurons in the Substantia Nigra of the mesencephalon leading to the absence of dopamine in the striatum and other basal ganglia. This in turn leads to aberrant enhanced neuronal activity in the striatum and basal ganglia, which produces the clinical symptoms.
At present there is no cure for neurodegenerative diseases with Parkinsonian Syndromes, but a variety of medications provide dramatic relief from the symptoms. Usually, patients are given Levodopa combined with carbidopa. Carbidopa delays conversion of Levodopa into dopamine until it reaches the brain. Nerve cells can use Levodopa to produce dopamine and replenish the brain's dwindling supply. Although Levodopa helps three-quarters parkinsonian patients, not all symptoms respond equally to the drug. Bradykinesia and rigidity respond best, while tremor may be marginally reduced. Problems with balance and other symptoms may not be alleviated at all.
Anticholinergics may help control tremor and rigidity. Other drugs, such as, bromocriptine, pramipexole, and ropinirole, mimic the role of dopamine in the brain, causing the neurons to react as they would to dopamine. An antiviral drug, amantadine, also appears to reduce symptoms. In May 2006, the FDA approved rasagiline (AZILECT®) to be used along with Levodopa for patients with advanced neurodegenerative diseases with Parkinsonian Syndromes or as a single-drug treatment for early neurodegenerative diseases with Parkinsonian Syndromes. A surgical treatment (i.e. deep brain stimulation applied to the sub-thalamic nucleus) is another recent option that can be considered in some PD patients. The treatment may act through a beneficial modulation of abnormal neural activities induced by the lack of brain dopamine.
In physiological conditions, the output neurons of the striatum, the Medium Spiny Neurons (MSNs) that comprises the vast majority of the neuronal population (over 95%) are inactive at rest as they have a much hyperpolarized membrane potential. They respond to synchronized cortical afferent activities only. This enables the motor cortex to generate striatal patterns needed for targeted movements. In neurodegenerative diseases with Parkinsonian Syndromes, the striatum is highly active, thereby perturbing the targeted movements' organization.
This hyperactivity was observed in mouse models of PD and is characterized by the generation of Giant GABAergic network driven Currents (GGCs) by MSNs of the Striatum (Dehorter et al. 2012; Dehorter et al., 2009). The causes of the dysfunction of these GABAergic signals are unclear but a link has been established with intracellular levels of chloride. Modulating intracellular levels of chloride may thus be a promising target for treating neurodegenerative diseases with Parkinsonian Syndromes.
The Applicant surprisingly showed that the use of antagonists of chloride co-transporters blocked aberrant GABAergic activity in the Striatum of a mouse model of PD as compared to the wild-type situation. Moreover, the Applicant showed in a clinical study that the use of antagonists of chloride co-transporters decreased the Parkinsonian Syndromes symptoms. The present invention thus relates to the use of a modulator of intracellular chloride level for treating neurodegenerative diseases with Parkinsonian Syndromes in a subject in need thereof.